D-EXP022

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Docking Dibenzalacetone Derivatives Against Tubulin Using PaDEL-ADV

Researchers: Andrew SID Lang, Jean-Claude Bradley, Matthew J McBride, and Anthony J Williams

Docking Run 22

Objective

To dock 325 dibenzalacetone derivatives (library 12) against tubulin in order to find replacement candidates for taxol (paclitaxel) that are easier (and cheaper) to synthesize from common starting materials found in abundance in the Bradley lab 2012-07-13.

Procedure

We followed the same procedure for docking with PaDEL-ADV as in Docking Run 19
1. We collated the product SMILES into a single file (lib012.smi)
2. We converted the SMILES to a collection of potential ligands (3D pdb files - correctly protonated) using ChemAxon's molconvert (zip)
molconvert -3 pdb:H lib012.smi -m -o lib12ligand.pdb
3. We performed docking using PaDEL-ADV - virtual screening completed in 4 hrs 39.5 mins (51s/mol)

Results

The affinities for all compounds in the library ranged from -10.3 to -5.8. The top ten candidates being:
Key
 CSID
 Product
 Aldehyde One
 Aldehyde Two
 MW
 VCClogP
 VCClogS
 ONSMP010 mpC
 Taxol Binding Affinity
1
 28190813
 O=C(\C=C\c2cc3c(c1c2cccc1)cccc3)\C=C\c2cc3c(c1c2cccc1)cccc3
 O=Cc2cc3c(c1c2cccc1)cccc3
 O=Cc2cc3c(c1c2cccc1)cccc3
 434.17
 8.09
 -9.22
 212
 -10.3
7
 NA
 O=C(\C=C\c2ccc1c(cccc1)c2)\C=C\c2cc3c(c1c2cccc1)cccc3
 O=Cc2ccc1c(cccc1)c2
 O=Cc2cc3c(c1c2cccc1)cccc3
 384.15
 7.32
 -8.87
 207
 -9.9
29
 NA
 O=C(\C=C\c1c2c(ccc1OC)cccc2)\C=C\c2cc3c(c1c2cccc1)cccc3
 O=Cc1c2c(ccc1OC)cccc2
 O=Cc2cc3c(c1c2cccc1)cccc3
 414.16
 7.14
 -8.82
 187
 -9.6
37
 NA
 O=C(\C=C\c1c2c(c(OC)cc1)ccc(OC)c2)\C=C\c2cc3c(c1c2cccc1)cccc3
 O=Cc1c2c(c(OC)cc1)ccc(OC)c2
 O=Cc2cc3c(c1c2cccc1)cccc3
 444.17
 7.13
 -8.73
 172
 -9.6
56
 NA
 O=C(\C=C\c1ccc(C)cc1C)\C=C\c2cc3c(c1c2cccc1)cccc3
 O=Cc1ccc(C)cc1C
 O=Cc2cc3c(c1c2cccc1)cccc3
 362.17
 6.73
 -8.57
 173
 -9.4
79
 NA
 O=C(\C=C\c1ccc(C(F)(F)(F))cc1)\C=C\c2cc3c(c1c2cccc1)cccc3
 O=Cc1ccc(C(F)(F)(F))cc1
 O=Cc2cc3c(c1c2cccc1)cccc3
 402.12
 6.61
 -7.81
 174
 -9.4
10
 4523376
 O=C(\C=C\c2ccc1c(cccc1)c2)\C=C\c2ccc1c(cccc1)c2
 O=Cc2ccc1c(cccc1)c2
 O=Cc2ccc1c(cccc1)c2
 334.14
 6.34
 -8.12
 192
 -9.3
92
 NA
 O=C(\C=C\c1cc(OC)ccc1)\C=C\c2cc3c(c1c2cccc1)cccc3
 O=Cc1cc(OC)ccc1
 O=Cc2cc3c(c1c2cccc1)cccc3
 364.15
 6.31
 -8.13
 175
 -9.3
191
 NA
 O=C(\C=C\c1cc(ccc1Cl)[N+]([O-])=O)\C=C\c2cc3c(c1c2cccc1)cccc3
 O=Cc1cc(ccc1Cl)[N+]([O-])=O
 O=Cc2cc3c(c1c2cccc1)cccc3
 413.08
 6.72
 -8.25
 175
 -9.3
301
 NA
 O=C(\C=C\c1ccc2OCOc2c1)\C=C\c2cc3c(c1c2cccc1)cccc3
 O=Cc1ccc2OCOc2c1
 O=Cc2cc3c(c1c2cccc1)cccc3
 378.13
 5.9
 -7.8
 183
 -9.3
Note that all these products are predicted to have low aqueous solubility (and predicted logP > 5 - a rule of 5 violation) as compared to the library as a whole, which ranges from -3.22 to -9.22 (our top hit). This low aqueous solubility is a concern as one of the reason why we are trying to find an alternative to taxol is its low aqueous solubility is a problem for delivery.

The top ligand is shown docked in the image below
20120808ligand1docked.png

Conclusion

Comparing the range of the top 10 ligand affinities for library12 (-9.3 to -10.3) with those of other docking runs: library7 - 117450 Ugi products (-10.9 to -11.4), library8 - 2175 Ugi products with the chiral side chain to paclitaxel (-9.8 to -10.8), library10 - 570 imines and 570 amines (-8.1 to -8.7); we see that DBA derivatives are good potential ligands, at least as compared to the imines and amines of library10. Considering their size, the Ugi products seem better candidates due to the large pocket size for tubulin, see the above image, though their binding affinities are not significantly better considering the size of the libraries docked.